Bivalency Erosion as a Unifying Mechanism of PFAS Inter‐ and Transgenerational Neurotoxicity

ABSTRACT Per‐ and polyfluoroalkyl substances (PFAS) are detected in the blood of over 98% of sampled populations in the United States and Europe. Inter‐ and transgenerational epigenetic effects have been demonstrated in at least three model organisms, yet no unifying molecular mechanism has been proposed. I present the Bivalency Erosion model. Legacy PFAS (such as PFOA and PFOS) generate a functional Fe 2+ deficit in the nucleus through iron redistribution and reactive oxygen species, inhibiting Fe (II)‐dependent JmjC demethylases at the catalytic level while suppressing both their transcription and that of H3K4me3 writers (MLL/SET1 complex). The result is coordinated loss of both H3K27me3 and H3K4me3 at bivalent HOX promoters, producing initially stochastic gene resolution that is subsequently consolidated into directed epigenetic silencing. Ether‐linked PFAS (GenX) may disrupt bivalency through the opposite vector (mark accumulation rather than erosion), suggesting that the critical lesion is loss of precise bivalent equilibrium regardless of direction. Loss of H3K4me3 releases DNMT3A autoinhibition, converting the histone lesion into heritable DNA methylation. The model integrates 12 convergent lines of evidence from 12 laboratories across six species. It is falsifiable by ChIP‐seq at HOX loci with dose–response and ascorbate rescue. This work is a theoretical literature synthesis containing no original experimental data.